5-aryl-indan-1-one oximes and analogs useful as progesterone receptor modulators

ABSTRACT

Compounds of formula I, wherein R 1 -R 9  and n are defined herein, and pharmaceutical compositions and kits containing these compounds are provided. 
     
       
         
         
             
             
         
       
     
     Also provided are methods of inducing contraception, providing hormone replacement therapy, treating cycle-related symptoms, or treating or preventing benign or malignant neoplastic disease using the compounds of formula I or formula II, wherein R 3 -R 5 , R 10 , and R 11  are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 USC 119(e) of prior U.S.Provisional Patent Application No. 60/718,408, filed Sep. 19, 2005.

BACKGROUND OF THE INVENTION

This invention relates to agonists and antagonists of the progesteronereceptor, their preparation and utility.

Intracellular receptors (IR) form a class of structurally related generegulators known as “ligand dependent transcription factors”(Mangelsdorf, D. J. etc. Cell, 83, 835, 1995). The steroid receptorfamily is a subset of the IR family, including progesterone receptor(PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoidreceptor (GR), and mineralocorticoid receptor (MR).

The natural hormone, or ligand, for the PR is the steroid progesterone,but synthetic compounds, such as medroxyprogesterone acetate orlevonorgestrel, have been made which also serve as PR ligands. Once aligand is present in the fluid surrounding a cell, it passes through themembrane via passive diffusion, and binds to the IR to create areceptor/ligand complex. This complex binds to specific gene promoterspresent in the cell's DNA. Once bound to the DNA the complex modulatesthe production of mRNA and the protein encoded by that gene.

A compound that binds to an IR and mimics the action of the naturalhormone is termed an agonist, whilst a compound which inhibits theeffect of the hormone is an antagonist.

PR agonists (natural and synthetic) are known to play an important rolein the health of women. PR agonists are used in birth controlformulations, either along or in the presence of an ER agonist. ERagonists are used to treat the symptoms of menopause, but have beenassociated with a proliferative effect on the uterus which can lead toan increased risk of uterine cancers. Co-administration of a PR agonistreduces/ablates that risk.

PR antagonists may also be used in contraception. In this context theymay be administered alone (Ulmann, et al., Ann. N.Y. Acad. Sci., 261,248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertilityand Sterility, 60, 610, 1993) or in combination with a partial ERantagonist such as tamoxifen (U.S. Pat. No. 5,719,136).

PR antagonists may also be useful for the treatment of hormone dependentbreast cancers (Horwitz, et al, Horm. Cancer, 283, 1996, pub:Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovariancancers. PR antagonists may also be useful for the treatment ofnon-malignant chronic conditions such as uterine fibroids (Murphy, etal, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, etal., Fertility and Sterility, 56, 402, 1991).

PR antagonists may also be useful in hormone replacement therapy forpost menopausal patients in combination with a partial ER antagonistsuch as tamoxifen (U.S. Pat. No. 5,719,136).

PR antagonists, such as mifepristone and onapristone, have been shown tobe effective in a model of hormone dependent prostate cancer, which mayindicate their utility in the treatment of this condition in men(Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).

SUMMARY OF THE INVENTION

In one aspect, a compound of formula I is provided, where R₁-R₉ and nare defined below.

In another aspect, a compound is provided selected from among5-[(1E)-1-(hydroxyimino)-3-methyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;(1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-one oxime; and apharmaceutically acceptable salt thereof.

In a further aspect, methods of inducing contraception, providinghormone replacement therapy, treating cycle-related symptoms, ortreating or preventing benign or malignant neoplastic disease areprovided using compounds of formula I.

In yet another aspect, methods of inducing contraception, providinghormone replacement therapy, treating cycle-related symptoms, ortreating or preventing benign or malignant neoplastic disease areprovided using compounds of formula II, wherein R₃-R₅, R₁₀, and R₁₁ aredefined below:

Other aspects and advantages will be readily apparent from the followingdetailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Novel progesterone receptor (PR) modulators and uses of the same intreating a variety of conditions are provided. The novel compounds havebeen shown to act as competitive inhibitors of progesterone binding tothe PR and act as PR modulators in functional models. These PRmodulators are thereby effective as PR agonists or PR antagonists.

As used herein, the terms “anti-progestational agent”, “anti-progestin”and “progesterone receptor antagonist” are understood to be synonymous.Similarly, “progestin”, “progestational agent”, and “progesteronereceptor agonist” are understood to refer to compounds of the sameactivity.

Compounds of formula I are provided:

wherein, R₁ and R₂ are, independently, selected from among H, halogen,C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ toC₈ cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; provided both of R₁ and R₂ are not H; or R₁ and R₂ are fusedto form (a), (b), or (c): (a) a carbon-based 3 to 6 membered saturatedspirocyclic ring; (b) a carbon-based 3 to 6 membered spirocyclic ringhaving in its backbone one or more carbon-carbon double bonds; or (c) acarbon-based 3 to 6 membered spirocyclic ring having in its backbone 1to 3 heteroatoms selected from among O, S, SO, SO₂, and NR^(C); whereinrings (a)-(c) are optionally substituted by 1 to 3 substituents selectedfrom among F, Cl, and C₁ to C₃ alkyl; R₃ is a 5 or 6 membered heteroarylring containing in its backbone 1 to 3 heteroatoms selected from amongO, S, SO, SO₂ and NR^(C) and substituted with 0 to 3 substituentsselected from among H, halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁to C₃ alkoxy, C₁ to C₃ alkylamino, C═NOR^(C), COR^(D), andNR^(C)COR^(D); R^(C) is absent, H, C₁ to C₄ alkyl, substituted C₁ to C₄alkyl, CN, or COR^(D); R^(D) is H, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, orC₁ to C₃ alkylamino; R₄ is H, halogen, CN, OH, NO₂, alkoxy, or loweralkyl; R₅ is H or lower alkyl; R₆, R₇, R₈, and R₉ are, independently, H,F, or C₁ to C₃ lower alkyl; n is 0 or 1; or a pharmaceuticallyacceptable salt thereof.

In one embodiment, a compound of formula I is provided, wherein R₁ andR₂ are, independently, H or C₁ to C₆ alkyl; R₃ is a 5 memberedheteroaryl ring containing in its backbone 1 NR^(C) heteroatom; R^(C) isC₁ to C₄ alkyl; R₄ is H; and R₅ is H or C₁ to C₃ alkoxy.

In another embodiment, a compound of formula I is provided, wherein R₅is H.

In a further embodiment, embodiment, a compound of formula I isprovided, wherein R₁ and R₂ are, independently, H or C₁ to C₆ alkyl; R₃is a 5 membered heteroayl ring containing in its backbone 1 NR^(C)heteroatom and substituted with 1 CN group; R^(C) is C₁ to C₄ alkyl; R₄is H; and R₅ is H or C₁ to C₃ alkoxy.

In yet another embodiment, a compound of formula I is provided, whereinR₁ and R₂ are, independently, C₁ to C₆ alkyl, CF₃, CF₂CF₃, or C₃ to C₆cycloalkyl; or R₁ and R₂ are fused to form a carbon-based 3 to 6membered saturated spirocyclic ring; R₄ is H, halogen, CN, OH, or NO₂;R₅ is H, alkyl, or perfluoroalkyl; and R₆, R₇, R₈, and R₉ are,independently, H or F.

In still a further embodiment, a compound of formula I is provided,wherein R₃ is 1-methyl-2-cyanopyrrole.

In another embodiment, a compound of formula I is provided, wherein R₃is 3,5-dimethylisoxazole.

In a further embodiment, a compound of formula I is provided, wherein R₃is of the structure:

wherein, U is O, S, or NR^(C); R^(C) is H, C₁ to C₄ alkyl, or CORD; RDis C₁ to C₄ alkyl; X′ is selected from among halogen, CN, NO₂, C₁ to C₃alkyl, and C₁ to C₃ alkoxy; and Y′ is selected from among H and C₁ to C₄alkyl.

In yet another embodiment, a compound of formula I is provided, whereinR₃ is of the structure:

wherein, X¹ is N or CX²; and X² is halogen, CN, C₁ to C₃ alkoxy, or NO₂.

In yet a further embodiment, a compound of formula I is providedselected from among5-[(1E)-1-(hydroxyimino)-3-methyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;and (1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-one oxime.

In still another embodiment, a compound of formula I is provided whichis5-[(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-methyl-1H-pyrrole-2-carbonitrile.

The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1 to about8 carbon atoms, and desirably 1 to about 6 carbon atoms (i.e., C₁, C₂,C₃, C₄, C₅ or C₆). Similarly, the term “lower alkyl” is used herein torefer to alkyl groups as just described, but having 1 to about 3 carbonatoms. Unless otherwise specified, the alkyl groups are not substituted.

The term “cycloalkyl” is used herein to an alkyl group as justdescribed, but cyclic in structure and having 3 to about 8 carbon atoms.In one embodiment, a cycloalkyl group has 3 to about 8 carbon atoms. Inanother embodiment, a cycloalkyl group has about 3 to about 6 carbonatoms (i.e., C₃, C₄, C₅ or C₆).

The term “alkenyl” is used herein to refer to both straight- andbranched-chain alkyl groups having one or more carbon-carbon doublebonds and containing about 3 to about 8 carbon atoms. In one embodiment,the term alkenyl refers to an alkyl group having 1 or 2 carbon-carbondouble bonds. In a further embodiment, an alkenyl group has about 2 toabout 8 carbon atoms. In another embodiment, an alkenyl group has about2 to about 6 carbon atoms. Unless otherwise specified, the alkenylgroups are not substituted.

The term “alkynyl” is used herein to refer to both straight- andbranched-chain alkyl groups having one or more carbon-carbon triple bondand having about 3 to about 8 carbon atoms. In one embodiment, the termalkynyl refers to an alkyl group having 1 or 2 carbon-carbon triplebonds and having about 3 to about 6 carbon atoms. Unless otherwisespecified, the alkynyl groups are not substituted.

The terms “substituted alkyl”, “substituted alkenyl”, “substitutedalkynyl”, and “substituted cycloalkyl” refer to alkyl, alkenyl, alkynyl,and cycloalkyl groups, respectively, having one or more substituentsincluding, without limitation, halogen, CN, OH, NO₂, amino, aryl,heterocyclic, substituted aryl, substituted heterocyclic, alkoxy,aryloxy, substituted alkoxy, alkylcarbonyl, alkylcarboxy, alkylamino, orarylthio. These substituents may be attached to any carbon of an alkyl,alkenyl, alkynyl or cycloalkyl group provided that the attachmentconstitutes a stable chemical moiety.

The term “acyl” as used herein refers to a carbonyl substituent, i.e., aC(O)(R) group where R is a straight- or branched-chain hydrocarbon groupincluding, without limitation, alkyl, alkenyl, and alkynyl groups. Inone embodiment, the R groups have 1 to about 8 carbon atoms, and in afurther embodiment 1 to about 6 carbon atoms. The term “substitutedacyl” refers to an acyl group which is substituted with 1 or more groupsincluding halogen, CN, OH, and NO₂.

The term “aryl” as used herein refers to an aromatic system which caninclude a single ring or multiple aromatic rings fused or linkedtogether where at least one part of the fused or linked rings forms theconjugated aromatic system. The aryl groups include, but are not limitedto, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl,phenanthryl, indene, benzonaphthyl, fluorenyl, and carbazolyl.Desirably, the aryl group is an optionally substituted phenyl group.

The term “substituted aryl” refers to an aryl group which is substitutedwith one or more substituents including halogen, CN, OH, NO₂, amino,alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylcarbonyl,alkylcarboxy, alkylamino, and arylthio, which groups can be optionallysubstituted. Desirably, a substituted aryl group is substituted with 1to about 4 substituents.

The term “heteroaryl,” as used herein, refers to an optionallysubstituted, mono-, di-, tri-, or other multicyclic aromatic ring systemthat includes at least one, and desirably from 1 to about 4 heteroatomring members including sulfur, oxygen and nitrogen. In one embodiment, aheteroaryl group can contain about 3 to about 50 carbon atoms, includingall combinations and subcombinations of ranges and specific numbers ofcarbon atoms therein. In another embodiment, a heteroaryl group cancontain about 4 to about 10 carbons. Non-limiting examples of heteroarylgroups include, for example, pyrrolyl, furyl, pyridyl,1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl,benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl,benzimidazolyl, and isoxazolyl.

The term “substituted heteroaryl” refers to an heteroaryl group which issubstituted with one or more substituents including halogen, CN, OH,NO₂, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy.

The term “heterocyclic” as used herein refers to a stable 4- to7-membered monocyclic or multicyclic heterocyclic ring which issaturated or partially unsaturated. The heterocyclic ring has in itsbackbone carbon atoms and one or more heteroatoms including nitrogen,oxygen, and sulfur atoms. Desirably, the heterocyclic ring has 1 toabout 4 heteroatoms in the backbone of the ring. When the heterocyclicring contains nitrogen or sulfur atoms in the backbone of the ring, thenitrogen or sulfur atoms can be oxidized. The term “heterocyclic” alsorefers to multicyclic rings in which a heterocyclic ring is fused to anaryl ring. The heterocyclic ring can be attached to the aryl ringthrough a heteroatom or carbon atom provided the resultant heterocyclicring structure is chemically stable.

A variety of heterocyclic groups are known in the art and include,without limitation, oxygen-containing rings, nitrogen-containing rings,sulfur-containing rings, mixed heteroatom-containing rings, fusedheteroatom containing rings, and combinations thereof. The heterocyclicgroups are selected from, but not limited to, furyl, tetrahydrofuranyl,pyranyl, pyronyl, dioxinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,pyridyl, piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, azepinyl, triazinyl, pyrrolidinyl, azepinyl,oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl,oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl,diazepinyl, benzofuranyl, thionapthene, indolyl, benazazolyl,purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl,anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl, benzodiazonyl,napthylridinyl, benzothienyl, pyridopyridinyl, benzoxazinyl, xanthenyl,acridinyl, and purinyl rings.

The term “substituted heterocyclic” as used herein refers to aheterocyclic group having one or more substituents including halogen,CN, OH, NO₂, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio, whichgroups can be optionally substituted. Desirably, a substitutedheterocyclic group has 1 to 4 substituents.

The term “arylthio” as used herein refers to the S(aryl) group, wherethe point of attachment is through the sulfur-atom and the aryl groupcan be optionally substituted.

The term “alkoxy” as used herein refers to the O(alkyl) group, where thepoint of attachment is through the oxygen-atom and the alkyl group isoptionally substituted.

The term “thioalkoxy” as used herein refers to the S(alkyl) group, wherethe point of attachment is through the sulfur-atom and the alkyl groupis optionally substituted.

The term “aryloxy” as used herein refers to the O(aryl) group, where thepoint of attachment is through the oxygen-atom and the aryl group isoptionally substituted.

The term “alkylcarbonyl” as used herein refers to the C(O)(alkyl) group,where the point of attachment is through the carbon-atom of the carbonylmoiety and the alkyl group is optionally substituted.

The term “alkylcarboxy” as used herein refers to the C(O)O(alkyl) group,where the point of attachment is through the carbon-atom of the carboxymoiety and the alkyl group is optionally substituted.

The term “alkylamino” as used herein refers to both secondary andtertiary amines where the point of attachment is through thenitrogen-atom and the alkyl groups are optionally substituted. The alkylgroups can be the same or different.

The term “halogen” as used herein refers to Cl, Br, F, or I groups.

The compounds described herein encompass tautomeric forms of thestructures provided herein characterized by the bioactivity of the drawnstructures. Further, the compounds described herein can be used in theform of salts derived from pharmaceutically or physiologicallyacceptable acids, bases, alkali metals and alkaline earth metals.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids including, for example, acetic, propionic, lactic,citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic,phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids. Salts may also beformed from inorganic bases, desirably alkali metal salts including, forexample, sodium, lithium, or potassium, and organic bases, such asammonium salts, mono-, di-, and trimethylammonium, mono-, di- andtriethylammonium, mono-, di- and tripropyl-ammonium (iso and normal),ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,benzylammonium, dibenzylammonium, piperidinium, morpholinium,pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-iso-propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methyl-piperidinium, 1-ethyl-2-methylpiperidinium,mono-, di- and triethanolammonium, ethyl diethanolammonium,n-butylmonoethanolammonium, tris(hydroxymethyl)methyl-ammonium,phenylmonoethanolammonium, and the like.

Physiologically acceptable alkali salts and alkaline earth metal saltscan include, without limitation, sodium, potassium, calcium andmagnesium salts in the form of esters, and carbamates.

These salts, as well as other compounds described herein can be in theform of esters, carbamates and other conventional “pro-drug” forms,which, when administered in such form, convert to the active moiety invivo. In one embodiment, the prodrugs are esters. See, e.g., B. Testaand J. Caldwell, “Prodrugs Revisited: The “Ad Hoc” Approach as aComplement to Ligand Design”, Medicinal Research Reviews, 16(3):233-241,ed., John Wiley & Sons (1996).

As described herein, the compounds described herein and/or salts,prodrugs or tautomers thereof, are delivered in regimens therapeutic orprophylactic purposes, as described herein.

The compounds discussed herein also encompass “metabolites” which areunique products formed by processing the compounds described herein bythe cell or subject. Desirably, metabolites are formed in vivo.

The compounds described herein are readily prepared by one of skill inthe art according to the following schemes from commercially availablestarting materials or starting materials which can be prepared usingliterature procedures. These schemes show the preparation ofrepresentative compounds. Variations on these methods, or other methodsknown in the art, can be readily performed by one of skill in the artgiven the information provided herein.

As illustrated in Scheme I, access to ketones 2 can be achieved byreaction of an appropriately substituted benzoic acid or its derivativessuch as Weinreb amides 1 with a suitable organo lithium or Grignardreagent. The reaction can be executed in an aprotic solvent includingbut not limited to tetrahydrofuran (THF) or diethyl ether at a suitabletemperature ranging from −78° C. to room temperature under a blanket ofinert atmosphere such as nitrogen or argon. To prevent the formation ofcarbinol side products, a reversing quenching procedure (pouring thereaction mixture to a diluted aqueous acidic solution such as hydrogenchloride solution) is preferred. An alternative way to work up thereaction included but not limited to an addition of trialkylsilylchloride or equivalent to the reaction before quenching the reactionmixture with a diluted aqueous acidic solution. Cyclization of ketones 2to afford indanones 3 can be effected with a suitable Lewis acid such aspolyphosphoric acid (PPA) and aluminum chloride in an aprotic solventsuch as chlorobenzene, xylene, the Dowtherm® A reagent, and nitrobenzeneat the temperature ranging from room temperature to refluxing ofsolvent. Formation of 5-aryl indanones 4 can be achieved by a number ofcoupling reactions including Suzuki or Stille protocols. These reactionsare commonly performed in the presence of a transition metalliccatalyst, e.g., palladium or nickel complex often with phosphinoligands, e.g., triphenylphosphine (Ph₃P),1,1′-bis(diphenylphosphino)ferrocene (dppf), or1,2-bis(diphenylphosphino)ethane (dppe). Under this catalytic condition,an appropriately substituted aryl nucleophilic reagent, e.g., arylboronic acid, arylstannane, or aryl zinc compound, can be coupled with 3to produce 5-aryl indanones 4. The commonly used bases in the reactioninclude but not limited to sodium bicarbonate, sodium carbonate,potassium phosphate, barium carbonate, cesium fluoride, and potassiumacetate. The most commonly used solvents in these reactions includebenzene, toluene, dimethylformamide (DMF), isopropanol, ethanol,dimethoxyethane (DME), and ether. The coupling reaction is generallyexecuted under an inert atmosphere such as nitrogen or argon attemperatures ranging from room temperature to 95° C. In the case when anappropriate aryl nucleophilic reagent is not available, the 5-halogen of3 can be converted to the borate or stannane, which can be coupled withan appropriate aryl halide such as aryl bromide or aryl iodide using anycoupling reaction described above to yield compounds 4. Conversion ofketones 4 to the compounds, 5, can be readily achieved by treating 4with a suitable hydroxylamine reagent such as hydroxylamine hydrogenchloride salt in an appropriate solvent such as ethanol and water at thetemperature ranging from ambient temperature to the refluxingtemperature of the solvent.

Alternatively, indanones as well as their six-member ring analogs,3,4-dihydro-2H-naphthalen-1-ones 7, can be furnished from appropriatelysubstituted 3-phenyl-propionic acids or 4-phenyl-butyric acids 6 asdepicted in scheme II. Preferably, acids 6 are activated by convertedinto their corresponding carbonyl chloride or anhydrides by reactingwith a suitable agent such as thionyl chloride or oxalyl chloride. Theactivated intermediates can be then in situ cyclized to form 7 using aFriedel-Crafts acylation protocol by addition of an appropriate Lewisacid such aluminum chloride or tin chloride in a suitable solvent suchas benzene, chlorobenzene, and nitrobenzene at the temperature rangingfrom room temperature to refluxing of the solvent used. Formation of5-aryl indanones or 6-aryl 3,4-dihydro-2H-naphthalen-1-ones 8, the keyintermediates led to the compounds 5, can be readily effected usingtypical aforementioned coupling procedures as illustrated in Scheme I.

Indanones or 3,4-dihydro-2H-naphthalen-1-ones 7 can also be prepared viaoxidation of appropriately substituted indans or1,2,3,4-tetrahydro-naphthalenes 9 using a suitable oxidant such aschromium (VI) oxide or manganese (IV) oxide in a suitable solvent suchas water and acetic acid as depicted in scheme III. Conversion of 7 to8, the key intermediates to the compounds described herein, can bereadily effected via the aforementioned coupling protocols.

Acyclic 1-(4-substituted-phenyl)-alkanones 11 can be furnished fromreaction of an appropriately substituted benzoic acid or its suitablederivative such as Weinreb amide 10 with a suitable organo lithium orGrignard reagent as illustrated in scheme IV and this transformation canbe executed aforementioned for the preparation of ketones 2 in scheme I.Followed the same coupling procedures as described in scheme I, the keyketone intermediates 12, can be furnished by reacting ketones 11 with anappropriate aryl nucleophilic reagent such as aryl boronic acidfollowing aforementioned coupling protocol in scheme I. Followed thesame procedure aforementioned in scheme I, the compounds 13 can beeffected from ketones 12 by treatment of 12 with a suitablehydroxylamine reagent.

Also included are pharmaceutical compositions containing one or morecompounds described herein and a pharmaceutically acceptable carrier orexcipient. Also included are methods of treatment which includeadministering to a mammal a pharmaceutically effective amount of one ormore compounds as described as progesterone receptor modulators.

The compounds described herein may be combined with one or morepharmaceutically acceptable carriers or excipients, for example,solvents, diluents and the like. Suitably, the compounds describedherein are formulated for delivery to a subject by any suitable routeincluding, e.g., transdermal, mucosal (intranasal, buccal, vaginal),oral, parenteral, among others. A variety of suitable delivery devicescan be utilized and include, without limitation, tablets, caplets,capsules, gel tabs, dispersible powders, granules, suspensions,injectable solutions, transdermal patches, topical creams or gels, andvaginal rings, among others.

One particularly desirable pharmaceutical composition, from thestandpoint of ease of preparation and administration, are solidcompositions, particularly tablets and hard-filled or liquid-filledcapsules. Oral administration of the compounds is most desirable.

The compounds described herein may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin. Liquid carriers include sterile water,polyethylene glycols, non-ionic surfactants and edible oils such ascorn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, butylatedhydroxytoluene (BHT) andbutylatedhydroxyanisole (BHA).

When formulated for oral delivery, the compound described herein can bein the form of a tablet, capsule, caplet, gel tab, dispersible powders,granules, or suspensions. In one embodiment, the compound can becombined with suspending agents, including about 0.05 to about 5% ofsuspending agent, syrups containing, for example, about 10 to about 50%of sugar, and/or elixirs containing, for example, about 20 to about 50%ethanol, and the like.

The compounds described herein may also be administered parenterally orintraperitoneally. Solutions or suspensions of the compounds describedherein as a free base or pharmacologically acceptable salt can beprepared in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid, polyethylene glycols and mixtures thereof in oils. In oneembodiment, the solutions or suspensions containing a compound describedherein can contain about 0.05 to about 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, about 25 to about 90% of the compound in combination with thecarrier. Desirably, the pharmaceutical preparation contains about 5% and60% by weight of the compound.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringe ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

The compounds described herein may also be administered via a vaginalring. Suitably, use of the vaginal ring is timed to cycle to which thecompound is being administered, including a 28-day cycle. However, thevaginal ring can be inserted for longer or shorter periods of time. See,U.S. Pat. Nos. 5,972,372; 6,126,958; and 6,125,850, which are herebyincorporated by reference, for formulations of the vaginal ring that canbe used.

The compound described herein can also be delivered via a transdermalpatch. Suitably, use of the patch is timed to the length of the cycle,including a 28 day cycle. However, the patch can remain in place forlonger or shorter periods of time.

These compounds can be utilized in methods of contraception, hormonereplacement therapy, the treatment and/or prevention of benign andmalignant neoplastic disease including uterine myometrial fibroids,endometriosis, benign prostatic hypertrophy; carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate,pituitary, meningioma and other hormone-dependent tumors, and thetreatment of cycle related symptoms, dysmenorrheal, dysfunctionaluterine bleeding, symptoms of premenstrual syndrome and premenstrualdysphoric disorder, and for inducing amenorrhea. Additional uses of thepresent progesterone receptor modulators include the synchronization ofestrus in livestock. In one embodiment, the neoplastic disease ishormone-dependent.

The term “cycle-related symptoms” as used herein refers to psychologicaland physical symptoms associated with a woman's menstrual cycle arisingin the luteal phase of the menstrual cycle. It has been reported thatmost women report experiencing cycle-related symptoms. The symptomsgenerally disappear after the onset of menstruation, and the patient isfree from symptoms during the rest of the follicular phase. The cyclicalnature of the symptom variations is characteristic of cycle-relatedsymptoms.

Cycle-related symptoms occur in about 95% of women who experience somephysical or mood changes with their menstrual cycles. Only aboutone-third of those women experiences moderate to severe cycle-relatedsymptoms. Women vary in the number, type, severity, and pattern ofsymptoms before menstruation. One thing common to all the types ofcyclic-related symptoms is the decrease or elimination of the symptomsin the two weeks after menstruation up to ovulation.

The term “cycle-related symptoms” refers to psychological symptoms (forexample, mood change, irritability, anxiety, lack of concentration, ordecrease in sexual desire) and physical symptoms (for example,dysmenorrhea, breast tenderness, bloating, fatigue, or food cravings)associated with a woman's menstrual cycle. Cycle-related symptoms occurafter ovulation but before menses and usually terminate at the start ofthe menstrual period or shortly thereafter. Cycle-related symptomsinclude, but are not limited to, dysmenorrhea and moderate to severecycle-related symptoms.

When utilized for these purposes, the compounds of formulas I or II canbe administered in combination with other agents, as well as incombination with each other. Such agents include, without limitation,progestins, antiprogestins, estrogens, among others. Progestins caninclude, without limitation, tanaproget, levonorgestrel, norgestrel,desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindroneacetate, norgestimate, osaterone, cyproterone acetate, trimegestone,dienogest, drospirenone, nomegestrol, (17-deacetyl)norgestimate.Estrogens can include, without limitation, ethinyl estradiol.

In one embodiment, a patient or subject being treated is a mammaliansubject and typically a female. Desirably, the subject is a human.However, as used herein, a female can include non-human mammals, e.g.,cattle or livestock, horses, pigs, domestic animals, etc.

Methods of inducing contraception, providing hormone replacementtherapy, or treating cycle-related symptoms are provided, includingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of the structure:

wherein, R₁ and R₂ are, independently, selected from among H, halogen,C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ toC₈ cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; or R₁ and R₂ are fused to form (a), (b), or (c): (a) acarbon-based 3 to 6 membered saturated spirocyclic ring; (b) acarbon-based 3 to 6 membered spirocyclic ring having in its backbone oneor more carbon-carbon double bonds; or (c) a carbon-based 3 to 6membered spirocyclic ring having in its backbone 1 to 3 heteroatomsselected from among O, S, SO, SO₂, and NR^(C); wherein rings (a)-(c) areoptionally substituted by 1 to 3 substituents selected from among F, Cl,and C₁ to C₃ alkyl; R₃ is aryl, substituted aryl, or a 5 or 6 memberedheteroayl ring containing in its backbone 1 to 3 heteroatoms selectedfrom among O, S, SO, SO₂ and NR^(C) and substituted with 0 to 3substituents selected from among H, halogen, CN, NO₂, OH, amino, C₁ toC₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ alkylamino, C═NOR^(C), COR^(D), andNR^(C)COR^(D); R^(C) is absent, H, C₁ to C₄ alkyl, substituted C₁ to C₄alkyl, CN, or COR^(D); R^(D) is H, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, orC₁ to C₃ alkylamino; R₄ is H, halogen, CN, OH, NO₂, alkoxy, or loweralkyl; R₅ is H or lower alkyl; R₆, R₇, R₈, and R₉ are, independently, H,F, or C₁ to C₃ lower alkyl; n is 0 or 1; or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the compound of formula I utilized in the method isselected from among5-[(1E)-1-(hydroxyimino)-3-methyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;(1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-one oxime;3-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]benzonitrile;4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]benzonitrile;3-fluoro-5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]benzonitrile;(1E)-5-(4-acetylphenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(3-acetylphenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(2-acetylphenyl)-3,3-dimethylindan-1-one oxime;4-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]benzonitrile;3-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]benzonitrile;(1E)-5-(4-chlorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-3,3-dimethyl-5-(4-methylphenyl)indan-1-one oxime;(1E)-5-(4-methoxyphenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(3-chlorophenyl)-3,3-dimethylindan-1-one oxime;1E)-3,3-dimethyl-5-(3-methylphenyl)indan-1-one oxime;(1E)-5-(3-methoxyphenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(3,5-dichlorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(2-chlorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(3,4-dichlorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(2,3-dichlorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(2,5-dichlorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-5-(2,4-dichlorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-3,3-dimethyl-5-phenylindan-1-one oxime;(1E)-5-(3-chloro-4-fluorophenyl)-3,3-dimethylindan-1-one oxime;(1E)-3,3-dimethyl-5-[3-(trifluoromethyl)phenyl]indan-1-one oxime;(1E)-3,3-dimethyl-5-[4-(trifluoromethyl)phenyl]indan-1-one oxime;(1E)-5-[4-(dimethylamino)phenyl]-3,3-dimethylindan-1-one oxime;(1E)-5-[3-(dimethylamino)phenyl]-3,3-dimethylindan-1-one oxime;(1E)-5-(3,4-difluorophenyl)-3,3-dimethylindan-1-one oxime; and(1E)-5-[3-(ethylsulfonyl)phenyl]-3,3-dimethylindan-1-one oxime.

In another embodiment, the compound of formula I utilized in the methodis selected from among5-[(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-methyl-1H-pyrrole-2-carbonitrile;(1E)-6-(3-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime;3-[(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl]benzonitrile;(1E)-6-(3-chloro-4-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime;(1E)-6-(4-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime;(1E)-6-[3-(trifluoromethyl)phenyl]-3,4-dihydronaphthalen-1(2H)-oneoxime; (1E)-6-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime;(1E)-6-(3,4-difluorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime;(1E)-6-(3-methylphenyl)-3,4-dihydronaphthalen-1(2H)-one oxime; and(1E)-6-(3-methoxyphenyl)-3,4-dihydronaphthalen-1 (2H)-one oxime.

In a further embodiment, when utilized in the method, R₃ of compound Iis 3-cyanophenyl, 4-cyanophenyl, 3-chlorophenyl,3-chloro-4-fluoro-phenyl, 3-trifluoromethylphenyl, 3-fluorophenyl,3,4-difluorophenyl, 3-tolyl, 3-methoxyphenyl, 3-cyano-5-fluorophenyl,4-acetylphenyl, 3-acetylphenyl, 2-acetylphenyl, 4-tolyl,4-methoxyphenyl, 3,5-dichlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl,2,3-dichlorophenyl, 2,5-dichlorophenyl, phenyl, 4-trifluoromethylphenyl,4-dimethylaminophenyl, 3-dimethylaminophenyl, or 3-ethylsulfonylphenyl.

A method of inducing contraception, providing hormone replacementtherapy, treating cycle-related symptoms, and treating or preventingbenign or malignant neoplastic disease is provided includingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of formula II:

wherein, R₃ is aryl, substituted aryl, or a 5 or 6 membered heteroaylring containing in its backbone 1 to 3 heteroatoms selected among O, S,SO, SO₂ and NR^(C) and substituted with 0 to 3 substituents selectedfrom among H, halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁ to C₃alkoxy, C₁ to C₃ alkylamino, C═NOR^(C), COR^(D), and NR^(C)COR^(D); R₄is H, halogen, CN, OH, NO₂, or alkoxy; R₅ is H or lower alkyl; R₁₀ andR₁₁ are, independently, H, F, or C₁ to C₃ lower alkyl; or apharmaceutically acceptable salt thereof.

In one embodiment, when performing the method using the compound offormula II, R₁₀ and R₁₁ are, independently, H or C₁ to C₆ alkyl; R₃ is a5 membered heteroayl ring containing in its backbone 1 NR^(C)heteroatom; R^(C) is C₁ to C₄ alkyl; R₄ is H; and R₅ is H or C₁ to C₃alkoxy.

In another embodiment, when performing the methods using the compoundsof formula I or II, R₅ is H.

In a further embodiment, when performing the method using the compoundof formula II, R₁₀ and R₁₁ are, independently, H or C₁ to C₆ alkyl; R₃is a 5 membered heteroayl ring containing in its backbone 1 NR^(C)heteroatom and substituted with 1 CN group; R^(C) is C₁ to C₄ alkyl; R₄is H; and R₅ is H or C₁ to C₃ alkoxy.

In still another embodiment, when performing the methods using thecompounds of formula I or II, R₃ is a benzene ring containing 0 to 3substituents selected from among halogen, CN, C₁ to C₄ alkyl,substituted C₁ to C₄ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ thioalkoxy, substituted C₁to C₃ thioalkoxy, amino, C₁ to C₃ alkylamino, substituted C₁ to C₃alkylamino, NO₂, C₁ to C₃ perfluoroalkyl, 5 or 6 membered heteroayl ringcontaining in its backbone 1 to 3 heteroatoms, COR^(C), OCOR^(C), andNR^(D)COR^(C).

In yet a further embodiment, when performing the methods using thecompounds of formula I or II, R₃ is a benzene ring of the structure:

wherein, X is selected from among halogen, CN, C₁ to C₄ alkyl,substituted C₁ to C₄ alkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ thioalkoxy, substituted C₁to C₃ thioalkoxy, amino, C₁ to C₃ alkylamino, substituted C₁ to C₃alkylamino, NO₂, C₁ to C₃ perfluoroalkyl, 5 or 6 membered heteroayl ringcontaining in its backbone 1 to 3 heteroatoms, COR^(C), OCOR^(C), orNR^(D)COR^(C); Y and Z are independent substituents selected from amongH, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, and C₁ to C₃thioalkoxy.

In still another embodiment, when performing the methods using thecompounds of formula I or II, R₃ is of the structure:

wherein, X is selected from among halogen, CN, C₁ to C₃ alkoxy, C₁ to C₃alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heteroayl ringcontaining in its backbone 1 to 3 heteroatoms, and C₁ to C₃ thioalkoxy;Y is selected from among H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄alkyl, and C₁ to C₃ thioalkoxy.

In another embodiment, when performing the methods using the compoundsof formula I or II, R₃ is 3-cyanophenyl, 4-cyanophenyl, 3-chlorophenyl,3-chloro-4-fluoro-phenyl, 3-trifluoromethylphenyl, 3-fluorophenyl,3,4-difluorophenyl, 3-tolyl, 3-methoxyphenyl, 3-cyano-5-fluorophenyl,4-acetylphenyl, 3-acetylphenyl, 2-acetylphenyl, 4-tolyl,4-methoxyphenyl, 3,5-dichlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl,2,3-dichlorophenyl, 2,5-dichlorophenyl, phenyl, 4-trifluoromethylphenyl,4-dimethylaminophenyl, 3-dimethylaminophenyl, or 3-ethylsulfonylphenyl.

In still a further embodiment, when performing the methods using thecompounds of formula I or II, R₃ is 1-methyl-2-cyano-pyrrole.

In yet another embodiment, when performing the methods using thecompounds of formula I or II, R₃ is 3,5-dimethylisoxazole.

In a further embodiment, when performing the methods using the compoundsof formula I or II, R₃ is a 5 or 6 membered heteroayl ring containing inits backbone 1 to 3 heteroatoms selected from among O, S, SO, SO₂ andNR^(C) and substituted with 0 to 3 substituents selected from among H,halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃alkylamino, C═NOR^(C), COR^(D), and NR^(C)COR^(D); R^(C) is absent, H,C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, CN, or CORD; R^(D) is H, C₁to C₃ alkyl, C₁ to C₃ alkoxy, or C₁ to C₃ alkylamino.

In still another embodiment, when performing the methods using thecompounds of formula I or II, R₁ and R₂ are, independently, C₁ to C₆alkyl, CF₃, CF₂CF₃, or C₃ to C₆ cycloalkyl; or R₁ and R₂ are fused toform a carbon-based 3 to 6 membered saturated spirocyclic ring; R₄ is H,halogen, CN, OH, or NO₂; R₅ is H, alkyl, or perfluoroalkyl; and R₆, R₇,R₈, and R₉ are, independently, H or F.

In yet another embodiment, when performing the methods, the compound isselected from among4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-3-carbonitrile;5-{4-[((E)-N-hydroxyethanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile;5-{4-[(Z)-(hydroxyimino)methyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile;4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-4-carbonitrile;4′-[(E)-(hydroxyimino)methyl]-3′-methyl-1,1′-biphenyl-3-carbonitrile;4′-[(E)-(hydroxyimino)methyl]-3′-methyl-1,1′-biphenyl-4-carbonitrile;5-{4-[(E)-(hydroxyimino)methyl]-3-methylphenyl}-1-methyl-1H-pyrrole-2-carbonitrile;5-{4-[(1E)-N-hydroxypropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile;5-{4-[(1E)-N-hydroxy-2,2-dimethylpropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile;and5-{4-[(1E)-N-methoxy-2,2-dimethylpropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile.

The effective dosage of the compounds described herein may varydepending on the particular compound employed, the mode ofadministration and the severity of the condition being treated. However,in general, satisfactory results are obtained when the compounds areadministered at a daily dosage of about 0.5 to about 500 mg/kg of animalbody weight, about 1 to about 400 mg/kg, about 5 to about 300 mg/kg,about 10 to about 250 mg/kg, about 50 to about 200 mg/kg, or about 100to 150 mg/kg. For most large mammals, the total daily dosage is fromabout 1 to 100 mg. In one embodiment, the total daily dosage is fromabout 2 to 80 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation.

As previously noted, the compounds may be administered via a vaginalring. Suitably, use of the vaginal ring is timed to the 28 day cycle. Inone embodiment, the ring is inserted into the vagina, and it remains inplace for 3 weeks. During the fourth week, the vaginal ring is removedand menses occurs. The following week a new ring is inserted to be wornanother 3 weeks until it is time for the next period. In anotherembodiment, the vaginal ring is inserted weekly, and is replaced for 3consecutive weeks. Then, following 1 week without the ring, a new ringis inserted to begin a new regimen. In yet another embodiment, thevaginal ring is inserted for longer or shorter periods of time.

Further, the previously mentioned patch is applied via a suitableadhesive on the skin, where it remains in place for 1 week and isreplaced weekly for a total period of 3 weeks. During the fourth week,no patch is applied and menses occurs. The following week a new patch isapplied to be worn to begin a new regimen. In yet another embodiment,the patch remains in place for longer, or shorter periods of time.

When used for contraception, the method typically includes delivering adaily dosage unit containing a compound for 28 consecutive days to afemale of child-bearing age. Desirably, the method includes deliveringthe compound over a period of 21 to 27 consecutive days followed by 1 to7 consecutive days in which no effective amount or no amount of thecompound is delivered. Optionally, the period of 1 to 7 days in which noeffective amount of the compound is delivered to the subject can involvedelivery of a second phase of daily dosage units of 1 to 7 days of apharmaceutically acceptable placebo. Alternatively, during this “placeboperiod”, no placebo is administered.

In another embodiment, the method includes delivering a compounddescribed herein for 21 consecutive days followed by 7 days in which noeffective amount of the compound is delivered. Optionally, during these7 days, a second phase of 7 daily dosage units of an orally andpharmaceutically acceptable placebo can be delivered. The compound mayoptionally be administered in combination with a progestin,antiprogestin, estrogen, or combination thereof.

In a further embodiment, the method includes delivering a compounddescribed herein for 23 consecutive days followed by 5 days in which noeffective amount of the compound is delivered. Optionally, during these5 days, a second phase of 5 daily dosage units of an orally andpharmaceutically acceptable placebo can be delivered. The compound mayoptionally be administered in combination with a progestin,antiprogestin, estrogen, or combination thereof.

In yet another embodiment, the method includes delivering a compounddescribed herein for 25 consecutive days followed by 3 days in which noeffective amount of the compound is delivered. Optionally, during these3 days, a second phase of 3 daily dosage units of an orally andpharmaceutically acceptable placebo can be delivered. The compounddescribed herein may optionally be administered in combination with aprogestin, antiprogestin, estrogen, or combination thereof.

In still a further embodiment, the method includes delivering a compounddescribed herein for 27 consecutive days followed by 1 day in which noeffective amount of the compound is delivered. Optionally, a secondphase of 1 daily dosage unit of an orally and pharmaceuticallyacceptable placebo can be delivered. The compound may optionally beadministered in combination with a progestin, antiprogestin, estrogen,or combination thereof.

In another embodiment, a method of contraception includes administeringto a female of child bearing age for 28 consecutive days: (a) a firstphase of from 14 to 24 daily dosage units of a progestational agentequal in progestational activity to about 35 to about 100 μglevonorgestrel; (b) a second phase of from 1 to 11 daily dosage units,at a daily dosage of from about 2 to 50 mg, of a compound of formula I,formula II, or combination thereof; and (c) optionally, a third phase ofdaily dosage units of an orally and pharmaceutically acceptable placebofor the remaining days of the 28 consecutive days in which noantiprogestin, progestin or estrogen is administered; wherein the totaldaily dosage units of the first, second and third phases equals 28.

In yet a further embodiment, a method of contraception includesadministering to a female of child bearing age for 28 consecutive days:(a) a first phase of from 14 to 24 daily dosage units of a compound offormula I, formula II, or combination thereof; (b) a second phase offrom 1 to 11 daily dosage units of an antiprogestin; and (c) optionally,a third phase of daily dosage units of an orally and pharmaceuticallyacceptable placebo for the remaining days of the 28 consecutive days inwhich no antiprogestin, progestin or estrogen is administered; whereinthe total daily dosage units of the first, second and third phasesequals 28.

In yet a further embodiment, a method of contraception is provided whichincludes administering to a female of child bearing age for 28consecutive days: (a) a first phase of from 14 to 24 daily dosage unitsof a progestational agent equal in progestational activity to about 35to about 100 μg levonorgestrel; (b) a second phase of from 1 to 11 dailydosage units, at a daily dosage of from about 2 to 50 mg, of a compoundof (i) or (ii): (i) a compound of formula I:

wherein R₁ and R₂ are, independently, selected from among H, halogen, C₁to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; provided both of R₁ and R₂ are not H; or R₁ and R₂ are fusedto form (a), (b), or (c): (a) a carbon-based 3 to 6 membered saturatedspirocyclic ring; (b) a carbon-based 3 to 6 membered spirocyclic ringhaving in its backbone one or more carbon-carbon double bonds; or (c) acarbon-based 3 to 6 membered spirocyclic ring having in its backbone 1to 3 heteroatoms selected from among O, S, SO, SO₂, and NR^(C); whereinrings (a)-(c) are optionally substituted by 1 to 3 substituents selectedfrom among F, Cl, and C₁ to C₃ alkyl; R₃ is a 5 or 6 membered heteroaylring containing in its backbone 1 to 3 heteroatoms selected from amongO, S, SO, SO₂ and NR^(C) and substituted with 0 to 3 substituentsselected from among H, halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁to C₃ alkoxy, C₁ to C₃ alkylamino, C═NOR^(C), COR^(D), andNR^(C)COR^(D); R^(C) is absent, H, C₁ to C₄ alkyl, substituted C₁ to C₄is alkyl, CN, or CORD; RD is H, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, or C₁to C₃ alkylamino; R₄ is H, halogen, CN, OH, NO₂, alkoxy, or lower alkyl;R₅ is H or lower alkyl; R₆, R₇, R₈, and R₉ are, independently, H, F, orC₁ to C₃ lower alkyl; n is 0 or 1; or (ii) a compound of formula II:

wherein, R₃ is aryl, substituted aryl, or a 5 or 6 membered heteroaylring containing in its backbone 1 to 3 heteroatoms selected from amongO, S, SO, SO₂ and NR^(C) and substituted with 0 to 3 substituentsselected from among H, halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁to C₃ alkoxy, C₁ to C₃ alkylamino, C═NOR^(C), COR^(D), andNR^(C)COR^(D); R₄ is H, halogen, CN, OH, NO₂, or alkoxy; R₅ is H orlower alkyl; R₁₀ and R₁₁ are, independently, H, F, or C₁ to C₃ loweralkyl; and (c) optionally, a third phase of daily dosage units of anorally and pharmaceutically acceptable placebo for the remaining days ofthe 28 consecutive days in which no antiprogestin, progestin or estrogenis administered; wherein the total daily dosage units of the first,second and third phases equals 28.

Also included are kits or packages of pharmaceutical formulationsdesigned for use in the regimens described herein. Suitably, the kitscontain one or more PR antagonist compounds as described herein.

Advantageously, for use in the kits, the compound is formulated for thedesired delivery vehicle and route. For example, the compound can beformulated for oral delivery, parenteral delivery, vaginal ring,transdermal delivery, or mucosal delivery, as discussed in detail above.The kit is preferably a pack (e.g. a blister pack) containing dailydoses arranged in the order in which they are to be taken.

In each of the regimens and kits described herein, it is preferred thatthe daily dosage of each pharmaceutically active component of theregimen remain fixed in each particular phase in which it isadministered. It is also understood that the daily dose units describedare to be administered in the order described, with the first phasefollowed in order by the optional phases, including any second and thirdphases. To help facilitate compliance with each regimen, it is alsopreferred that the kits contain the placebo described for the final daysof the cycle. It is further preferred that each package or kit contain apharmaceutically acceptable package having indicators for each day ofthe 28-day cycle, such as a labeled blister package, dial dispenser, orother packages known in the art.

These dosage regimens may be adjusted to provide the optimal therapeuticresponse. For example, several divided doses of each component may beadministered daily or the dose may be proportionally increased orreduced as indicated by the exigencies of the therapeutic situation. Inthe descriptions herein, reference to a daily dosage unit may alsoinclude divided units which are administered over the course of each dayof the cycle contemplated.

In one embodiment, the kit is designed for daily oral administrationover a 28-day cycle, desirably for one oral administration per day, andorganized so as to indicate a single oral formulation or combination oforal formulations to be taken on each day of the 28-day cycle. Desirablyeach kit will include oral tablets to be taken on each the daysspecified; desirably one oral tablet will contain each of the combineddaily dosages indicated. For example, a kit can contain 21 to 27 dailydosage units of an effective amount of the compound described hereinand, optionally, 1 to 7 daily dosage units of a placebo and otherappropriate components including, e.g., instructions for use.

In another embodiment, the kit is designed for weekly or monthlyadministration via a vaginal ring over a 28-day cycle. Suitably, such akit contains individual packaging for each of the vaginal rings, i.e.one to three, required for a monthly cycle and other appropriatecomponents, including, e.g., instructions for use.

In a further embodiment, the kit is designed for weekly or monthlyadministration via a transdermal patch over a 28-day cycle. Suitably,such a kit contains individual packaging for each of the patches, i.e.one to three, required for a monthly cycle and other appropriatecomponents including, e.g., instructions for use.

In still another embodiment, the kit is designed for parenteral deliveryof a compound described herein. Such a kit is typically designed fordelivery at home and may include needles, syringes, and otherappropriate packaging and instructions for use.

In yet another embodiment, the kit contains a compound described hereinin a gel or cream formulation. Optionally, the kit can includeappropriate packaging such as a tube or other container, an applicator,and/or instructions for use.

In a further embodiment, the kit includes (a) a first phase of from 14to 21 daily dosage units of a progestational agent equal inprogestational activity to about 35 to about 150 μg levonorgestrel; (b)a second phase of from 1 to 11 daily dosage units of a compound offormula I or II, each daily dosage unit containing said compound at adaily dosage of from about 2 to 50 mg, wherein said compound is (i) or(ii): (i) a compound of formula I:

wherein, R₁ and R₂ are, independently, selected from among H, halogen,C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ toC₈ cycloalkyl, aryl, substituted aryl, heteroaryl, and substitutedheteroaryl; provided both of R₁ and R₂ are not H; or R₁ and R₂ are fusedto form (a), (b), or (c): (a) a carbon-based 3 to 6 membered saturatedspirocyclic ring; (b) a carbon-based 3 to 6 membered spirocyclic ringhaving in its backbone one or more carbon-carbon double bonds; or (c) acarbon-based 3 to 6 membered spirocyclic ring having in its backbone 1to 3 heteroatoms selected among O, is S, SO, SO₂, and NR^(C); whereinrings (a)-(c) are optionally substituted by 1 to 3 substituents selectedfrom among F, Cl, and C₁ to C₃ alkyl; R₃ is a 5 or 6 membered heteroaylring containing in its backbone 1 to 3 heteroatoms selected from amongO, S, SO, SO₂ and NR^(C) and substituted with 0 to 3 substituentsselected from among H, halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁to C₃ alkoxy, C₁ to C₃ alkylamino, C═NOR^(C), COR^(D), andNR^(C)COR^(D); R^(C) is absent, H, C₁ to C₄ alkyl, substituted C₁ to C₄alkyl, CN, or COR^(D); R^(D) is H, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, orC₁ to C₃ alkylamino; R₄ is H, halogen, CN, OH, NO₂, alkoxy, or loweralkyl; R₅ is H or lower alkyl; R₆, R₇, R₈, and R₉ are, independently, H,F, or C₁ to C₃ lower alkyl; n is 0 or 1; or (ii) a compound of formulaII:

wherein, R₃ is aryl, substituted aryl, or a 5 or 6 membered heteroaylring containing in its backbone 1 to 3 heteroatoms selected from amongO, S, SO, SO₂ and NR^(C) and substituted with 0 to 3 substituentsselected from among H, halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁to C₃ alkoxy, C₁ to C₃ alkylamino, C═NOR^(C), COR^(D), andNR^(C)COR^(D); R₄ is H, halogen, CN, OH, NO₂, or alkoxy; R₅ is H orlower alkyl; R₁₀ and R₁₁ are, independently, H, F, or C₁ to C₃ loweralkyl; and (c) a third phase of daily dosage units of an orally andpharmaceutically acceptable placebo; wherein the total number of thedaily dosage units in the first phase, second phase and third phaseequals 28.

The following examples are illustrative only and are not intended to bea limitation.

EXAMPLES Example 14′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-3-carbonitrile

To a stirred solution of 4-bromobenzaldehyde (3.0 g, 16.2 mmol) inethanol (100 mL) and water (25 mL) was added sodium acetate (1.7 g, 21.0mmol) and hydroxylamine hydrochloride (1.4 g, 19.5 mmol). The resultingmixture was heated to reflux for 2 hours. The solution was allowed tocool to room temperature, concentrated, and filtered to give4-bromobenzaldehyde oxime (3.02 g, 93%). 4-Bromobenzaldehyde oxime (0.25g, 1.25 mmol) was added to a stirred solution of 3-cyanophenyl boronicacid (0.28 g, 1.87 mmol) in glyme (13 mL). Sodium carbonate (0.39 g,3.75 mmol) in water (2 mL) and tetrakis(triphenylphosphine) palladium(0) (0.07 g, 0.06 mmol) was added and the resulting solution was heatedto reflux for 3 hours. The solution was cooled to room temperature andpartitioned between a saturated ammonium chloride solution (100 mL) andethyl acetate (150 mL). The organic layer was separated, dried overmagnesium sulfate, filtered, and concentrated. The residue was purifiedon a silica gel column (20% ethyl acetate in hexane) and triturated withether to give 4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-3-carbonitrileas a white solid (0.17 g, 61%). MS m/z 223; HRMS: calcd forC₁₄H₁₀N₂O+H⁺, 223.08659; found (ESI, [M+H]⁺), 223.087; Anal. Calcd forC₁₄H₁₀N₂O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.49; H, 4.98; N,12.51.

Example 25-{4-[(1E)-N-hydroxyethanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile

To a stirred solution of 1-methyl-2-cyanopyrrole (1.6 g, 15 mmol) andtriisopropyl borate (7.0 mL, 30 mmol) in THF (45 mL) at 0° C. was addedlithiumdiisopropylamide (LDA—2.0 M in heptane/THF/ethylbenzene, 13.3 mL,26.6 mmol) in a dropwise fashion over 45 minutes. The resulting solutionwas stirred at 0° C. for 1 hour. To the solution was added1-(4-bromophenyl)-ethanone (1.0 g, 5 mmol) dissolved in glyme (45 mL),sodium carbonate (1.59 g, 15 mmol) dissolved in water (9 mL), andtetrakis(triphenylphosphine) palladium (0) (0.28 g, 0.25 mmol). Theresulting solution was heated to reflux for 1.5 hours. The solution wascooled to room temperature and partitioned between a saturated ammoniumchloride solution (50 mL) and ethyl acetate (80 mL). The organic layerwas separated, dried over magnesium sulfate, filtered, and concentrated.The residue was purified on a silica gel column (20% ethyl acetate inhexane) and triturated with ether to give5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile as a yellow solid(0.62 g, 55%). MS (ES) m/z 225.1; HRMS: calcd for C₁₄H₁₂N₂O+H⁺,225.1022; found (ESI, [M+H]⁺), 225.1039.

The title compound was prepared from5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile and hydroxylaminehydrochloride salt according to the procedure described in example 1. MS(ESI) m/z 240; HRMS: calcd for C₁₄H₁₃N₃O+H+, 240.11314; found (ESI,[M+H]⁺), 240.1126.

Example 35-[(1E)-1-(hydroxyimino)-3-methyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile

To a mixture of sodium chloride (1.23 g, 21.0 mmol) and aluminumchloride (5.0 g, 38.2 mmol) at 130° C. was added1-(4-bromophenyl)-4-chlorobutan-1-one (1.0 g, 3.82 mmol) and theresulting mixture was heated to 180° C. for 20 minutes. The mixture wasallowed to cool to room temperature and quenched by portionwise additionto a cold 1N HCl solution (150 mL). The mixture was extracted severaltimes with dichloromethane. The combined organic layers were separated,dried over magnesium sulfate, filtered, and concentrated to give5-bromo-3-methyl-indan-1-one (0.77 g, 89%).

1-Methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrileas an orange solid (0.65 g, 76%) was prepared from5-bromo-3-methyl-indan-1-one and 1-methyl-2-cyanopyrrole according tothe same coupling procedure as described in example 2. MS (ES) m/z251.2; Anal. Calcd for C₁₆H₁₄N₂O: C, 76.78; H, 5.64; N, 11.19. Found: C,76.49; H, 5.49; N, 11.10. HRMS: calcd for C₁₆H₁₄N₂O+H⁺, 251.1179; found(ESI, [M+H]⁺), 251.1179.

The title compound was prepared from1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrileand hydroxylamine hydrochloride according to the procedure described inexample 1. MS m/z 266; HRMS: calcd for C₁₆H₁₅N₃O+H⁺, 266.12879; found(ESI, [M+H]⁺), 266.1299; Anal. Calcd for C₁₆H₁₅N₃O: C, 72.43; H, 5.70;N, 15.84. Found: C, 71.86; H, 6.31; N, 15.47.

Example 45-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile

To a stirred solution of 1-(4-hydroxyphenyl)-3-methylbut-2-en-1-one (1.0g, 5.67 mmol) in dichlorobenzene (50 mL) was added aluminum chloride(1.97 g, 14.74 mmol). The mixture was heated to 150° C. for 4 hours.After cooled to room temperature, the reaction mixture was poured overice and extracted with dichloromethane (3×80 mL). The organic layerswere combined, dried over magnesium sulfate, filtered, and concentrated.The residue was purified on a silica gel column (20% ethyl acetate inhexane) to give 5-hydroxy-3,3-dimethylindan-1-one as a tan solid (0.32g, 32%). MS m/z 177.

A solution of 5-hydroxy-3,3-dimethylindan-1-one in anhydrous pyridine at0° C. was treated with triflic anhydride under an atmosphere ofnitrogen. After completion of reaction indicated by thin layerchromatography, the reaction solution was poured onto a mixture of iceand 6N aqueous HCl solution and extracted with diethyl ether. Theorganic layers were combined, washed with saturated aqueous sodiumbicarbonate solution, dried (MgSO₄), and concentrated to affordtrifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester thatwas used in the next step without further purification.

5-(3,3-Dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrilewas prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 1-methyl-2-cyanopyrroleaccording to the same coupling procedure as described in example 2. MS(ES) m/z 265.1. HRMS: calcd for C₁₇H₁₆N₂O+H⁺, 265.13354; found (ESI,[M+H]⁺), 265.1332.

To a stirred mixture of5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile(0.07 g, 0.26 mmol) in ethanol (1.6 mL)/water (0.4 mL) was added sodiumacetate (0.03 g, 0.34 mmol) and hydroxylamine hydrochloride (0.02 g,0.32 mmol). The resulting mixture was heated to reflux for 5 hours. Thesolution was allowed to cool to room temperature, diluted with water,and filtered to give5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrileas a white solid (0.04 g, 55%). MS (ES) m/z 280.1. HRMS: calcd forC₁₇H₁₇N₃O+H⁺, 280.14444; found (ESI, [M+H]⁺), 280.145.

Example 55-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared from1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrileand hydroxylamine hydrochloride according to the procedure described inexample 1. MS (ESI) m/z 252; HRMS: calcd for C₁₅H₁₃N₃O+H⁺, 252.11314;found (ESI, [M+H]⁺), 252.1133

Example 63-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]benzonitrile

To a stirred solution of 5-bromoindan-1-one oxime (0.25 g, 1.10 mmol) inglyme (11 mL) was added 3-cyanophenyl boronic acid (0.21 g, 1.44 mmol),sodium carbonate (0.35 g, 3.30 mmol) dissolved in deionized (D.I.) water(2 mL), and tetrakis(triphenylphosphine) palladium (0) (0.06 g, 0.05mmol). The resulting solution was heated to reflux for 2 hours. Thesolution was cooled to room temperature and partitioned between ammoniumchloride solution (sat.) and ethyl acetate. The organic layer was driedover magnesium sulfate, filtered, and concentrated. The residue waspurified on a silica gel column (20% ethyl acetate/hexane) andtriturated with ether to give3-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]benzonitrile as awhite solid (0.12 g, 43%). MS (ESI) m/z 249; HRMS: calcd forC₁₆H₁₂N₂O+H⁺, 249.10224; found (ESI, [M+H]⁺), 249.1033.

Example 74-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]benzonitrile

The title compound was prepared from 5-bromoindan-1-one oxime and4-cyanophenyl boronic acid according to the procedure described inexample 6. MS (ESI) m/z 249; HRMS: calcd for C₁₆H₁₂N₂O+H⁺, 249.10224;found (ESI, [M+H]⁺), 249.1021.

Example 85-{4-[(Z)-(hydroxyimino)methyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared from 4-bromobenzaldehyde and1-methyl-1H-pyrrole-2-carbonitrile according to the procedure describedin examples 1 and 2. MS m/z 226; HRMS: calcd for C₁₃H₁₁N₃O+H⁺,226.09749; found (ESI, [M+H]⁺), 226.0972; Anal. Calcd for C₁₃H₁₁N₃O: C,69.32; H, 4.92; N, 18.65. Found: C, 69.20; H, 5.44; N, 18.70.

Example 9 4′-[(E)-(hydroxyimino)methyl]-1,1′-biphenyl-4-carbonitrile

The title compound was prepared from 4-bromobenzaldehyde and4-cyanophenyl boronic acid according to the procedure described inexample 1. MS m/z 223; HRMS: calcd for C₁₄H₁₀N₂O+H⁺, 223.08659; found(ESI, [M+H]⁺), 223.0866; Anal. Calcd for C₁₄H₁₀N₂O: C, 75.66; H, 4.54;N, 12.60. Found: C, 75.48; H, 4.56; N, 12.37.

Example 104′-[(E)-(hydroxyimino)methyl]-3′-methyl-1,1′-biphenyl-3-carbonitrile

The title compound was prepared from 4-bromo-2-methylbenzaldehyde and3-cyanophenyl boronic acid according to the procedure described inexample 1. MS (ES) m/z 237.1; HRMS: calcd for C₁₅H₁₂N₂O+H⁺, 237.10224;found (ESI, [M+H]⁺), 237.1018.

Example 114′-[(E)-(hydroxyimino)methyl]-3′-methyl-1,1′-biphenyl-4-carbonitrile

The title compound was prepared from 4-bromo-2-methylbenzaldehyde and4-cyanophenyl boronic acid according to the procedure described inexample 1. MS (ES) m/z 237.2; HRMS: calcd for C₁₅H₁₂N₂O+H⁺, 237.10224;found (ESI, [M+H]⁺), 237.1028.

Example 125-{4-[(E)-(hydroxyimino)methyl]-3-methylphenyl)}-1-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared from 4-bromo-2-methylbenzaldehyde and1-methyl-1H-pyrrole-2-carbonitrile according to the procedure describedin examples 1 and 2. MS (ES) m/z 240.1; HRMS: calcd for C₁₄H₁₃N₃O+H⁺,240.11314; found (ESI, [M+H]⁺), 240.1134.

Example 135-{4-[(1E)-N-hydroxypropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared from 1-(4-bromophenyl)-propan-1-one and1-methyl-2-cyanopyrrole according to the procedure as described inexamples 1 and 2. MS (ESI) m/z 254; HRMS: calcd for C₁₅H₁₅N₃O+H⁺,254.12879; found (ESI, [M+H]⁺), 254.1295.

Example 14 (1E)-6-(3-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-chlorophenylboronic acid according to the procedure as described in example 1. MS(ES) m/z 272.1; HRMS: calcd for C₁₆H₁₄ClNO+H⁺, 272.08367; found (ESI,[M+H]⁺), 272.0845.

Example 155-[(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and1-methyl-1H-pyrrole-2-carbonitrile according to the procedure asdescribed in examples 1 and 2. MS m/z 266; HRMS: calcd for C₁₆H₁₅N₃O+H⁺,266.12879; found (ESI, [M+H]⁺), 266.1284.

Example 163-[(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl]benzonitrile

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-cyanophenyl boronicacid according to the procedure as described in example 1. MS (ESI) m/z263.

Example 17(1E)-6-(3-chloro-4-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and3-chloro-4-fluorophenyl boronic acid according to the procedure asdescribed in example 1. MS m/z 290.

Example 18 (1E)-6-(4-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 4-chlorophenylboronic acid according to the procedure as described in example 1. MSm/z 272.

Example 19(1E)-6-[3-(trifluoromethyl)phenyl]-3,4-dihydronaphthalen-1(2H)-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and3-(trifluoromethyl)phenyl boronic acid according to the procedure asdescribed in example 1. MS m/z 306.

Example 20 (1E)-6-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-fluorophenylboronic acid according to the procedure as described in example 1. MSm/z 256.

Example 21 (1E)-6-(3,4-difluorophenyl)-3,4-dihydronaphthalen-1(2H)-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3,4-difluorophenylboronic acid according to the procedure as described in example 1. MSm/z 274.

Example 22 (1E)-6-(3-methylphenyl)-3,4-dihydronaphthalen-1(2H)-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methylphenylboronic acid according to the procedure as described in example 1. MS(ESI) m/z 252.

Example 23 (1E)-6-(3-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methoxyphenylboronic acid according to the procedure as described in example 1. MS(ES) m/z 268.1.

Example 245-{4-[(1E)-N-hydroxy-2,2-dimethylpropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared from1-(4-bromophenyl)-2,2-dimethylpropan-1-one and 1-methyl-2-cyanopyrroleaccording to the procedure as described in examples 1 and 2. MS m/z 282;HRMS: calcd for C₁₇H₁₉N₃O+H⁺, 282.16009; found (ESI, [M+H]⁺), 282.1606.

Example 255-{4-[(1E)-N-methoxy-2,2-dimethylpropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile

To a stirred solution of5-{4-[(1E)-N-hydroxy-2,2-dimethylpropanimidoyl]-phenyl}-1-methyl-1H-pyrrole-2-carbonitrile(0.212 g, 0.75 mmol) in THF (7 mL) was added sodium hydride (0.03 g, 60%in mineral oil, 0.75 mmol) at 0° C. After the mixture was stirred for 10minutes, methyl iodide (0.8 mL, 1.28 mmol) was added and the resultingmixture was stirred overnight at room temperature. The reaction mixturewas then quenched with a saturated ammonium chloride solution (20 mL),and extracted several times with ethyl acetate (3×20 mL). The combinedorganic layers were dried over magnesium sulfate and concentrated. Theresidue was purified by a silica gel column (5% ethyl acetate in hexane)to afford5-{4-[(1E)-N-methoxy-2,2-dimethylpropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrileas a white solid (0.023 g, 10%). MS (ES) m/z 296.0; HRMS: calcd forC₁₈H₂₁N₃O+H⁺, 296.17574; found (ESI, [M+H]⁺), 296.1753.

Example 26 (1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3,5-dimethylisoxazol-4-ylboronic acid according to the procedure as described in example 1. MS(ES) m/z 271.1; HRMS: calcd for C₁₆H₁₈N₂O₂+H⁺, 271.14410; found (ESI,[M+H]⁺), 271.1442.

Example 273-fluoro-5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]benzonitrile

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-fluoro-5-cyanophenyl boronicacid according to the procedure as described in example 1. MS (ESI) m/z295; HRMS: calcd for C₁₈H₁₅FN₂O+H⁺, 295.12412; found (ESI, [M+H]⁺),295.1241.

Example 28 (1E)-5-(4-acetylphenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-acetylphenyl boronic acidaccording to the procedure as described in example 1. MS (ESI) m/z 294;HRMS: calcd for C₁₉H₁₉NO₂+H⁺, 294.14885; found (ESI, [M+H]⁺), 294.1493.

Example 29 (1E)-5-(3-acetylphenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-acetylphenyl boronic acidaccording to the procedure as described in example 1. MS (ESI) m/z 294;HRMS: calcd for C₁₉H₁₉NO₂+H⁺, 294.14885; found (ESI, [M+H]⁺), 294.1503.

Example 30 (1E)-5-(2-acetylphenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 2-acetylphenyl boronic acidaccording to the procedure as described in example 1. MS (ESI) m/z 294;HRMS: calcd for C₁₉H₁₉NO₂+H⁺, 294.14885; found (ESI, [M+H]⁺), 294.1498.

Example 314-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]benzonitrile

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-cyanophenyl boronic acidaccording to the procedure as described in example 1. MS (ESI) m/z 277;HRMS: calcd for C₁₈H₁₆N₂O+H⁺, 277.13354; found (ESI, [M+H]⁺), 277.1335.

Example 323-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]benzonitrile

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-cyanophenyl boronic acidaccording to the procedure as described in example 1. MS (ESI) m/z 277;HRMS: calcd for C₁₈H₁₆N₂O+H⁺, 277.13354; found (ESI, [M+H]⁺), 277.134.

Example 33 (1E)-5-(4-chlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-chlorophenyl boronic acidaccording to the procedure as described in example 1. MS m/z 286; HRMS:calcd for C₁₇H₁₆ClNO+H⁺, 286.09932; found (ESI, [M+H]⁺), 286.1003.

Example 34 (1E)-3,3-dimethyl-5-(4-methylphenyl)indan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-methylphenyl boronic acidaccording to the procedure as described in example 1. MS m/z 266; HRMS:calcd for C₁₈H₁₉NO+H⁺, 266.15394; found (ESI, [M+H]⁺), 266.1553.

Example 35 (1E)-5-(4-methoxyphenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-methoxyphenyl boronic acidaccording to the procedure as described in example 1. MS m/z 282; HRMS:calcd for C₁₈H₁₉NO₂+H⁺, 282.14885; found (ESI, [M+H]⁺), 282.1506.

Example 36 (1E)-5-(3-chlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-chlorophenyl boronic acidaccording to the procedure as described in example 1. MS m/z 286; HRMS:calcd for C₁₇H₁₆ClNO+H⁺, 286.09932; found (ESI, [M+H]⁺), 286.0993.

Example 37 (1E)-3,3-dimethyl-5-(3-methylphenyl)indan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-methylphenyl boronic acidaccording to the procedure as described in example 1. MS m/z 266; HRMS:calcd for C₁₈H₁₉NO+H⁺, 266.15394; found (ESI, [M+H]⁺), 266.1552.

Example 38 (1E)-5-(3-methoxyphenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-methoxyphenyl boronic acidaccording to the procedure as described in example 1. MS m/z 282; HRMS:calcd for C₁₈H₁₉NO₂+H⁺, 282.14885; found (ESI, [M+H]⁺), 282.15.

Example 39 (1E)-5-(3,5-dichlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3,5-dichlorophenyl boronic acidaccording to the procedure as described in example 1. MS m/z 320; HRMS:calcd for C₁₇H₁₅Cl₂NO+H⁺, 320.06034; found (ESI, [M+H]⁺), 320.0605.

Example 40 (1E)-5-(2-chlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 2-chlorophenyl boronic acidaccording to the procedure as described in example 1. MS m/z 286; HRMS:calcd for C₁₇H₁₆ClNO+H⁺, 286.09932; found (ESI, [M+H]⁺), 286.0993.

Example 41 (1E)-5-(3,4-dichlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3,4-dichlorophenyl boronic acidaccording to the procedure as described in example 1. MS m/z 320; HRMS:calcd for C₁₇H₁₅Cl₂NO+H⁺, 320.06034; found (ESI, [M+H]⁺), 320.0597.

Example 42 (1E)-5-(2,3-dichlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 2,3-dichlorophenyl boronic acidaccording to the procedure as described in example 1. MS m/z 320; HRMS:calcd for C₁₇H₁₅Cl₂NO+H⁺, 320.06034; found (ESI, [M+H]⁺), 320.0605.

Example 43 (1E)-5-(2,5-dichlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 2,5-dichlorophenyl boronic acidaccording to the procedure as described in example 1. MS (ES) m/z 319.9;HRMS: calcd for C₁₇H₁₅Cl₂NO+H⁺, 320.06034; found (ESI, [M+H]⁺),320.0615.

Example 44 (1E)-5-(2,4-dichlorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 2,4-dichlorophenyl boronic acidaccording to the procedure as described in example 1. MS (ES) m/z 320.0;HRMS: calcd for C₁₇H₁₅Cl₂NO+H⁺, 320.06034; found (ESI, [M+H]⁺),320.0602.

Example 45 (1E)-3,3-dimethyl-5-phenylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and phenyl boronic acid according tothe procedure as described in example 1. MS (ES) m/z 252.0; HRMS: calcdfor C₁₇H₁₇NO+H⁺, 252.13829; found (ESI, [M+H]⁺), 252.1397.

Example 46 (1E)-5-(3-chloro-4-fluorophenyl)-3,3-dimethylindan-1-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-chloro-4-fluorophenyl boronicacid according to the procedure as described in example 1. MS (ES) m/z304.0; HRMS: calcd for C₁₇H₁₅ClFNO+H⁺, 304.08990; found (ESI, [M+H]⁺),304.0901.

Example 47 (1E)-3,3-dimethyl-5-[3-(trifluoromethyl)phenyl]indan-1-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-(trifluoromethyl)phenylboronic acid according to the procedure as described in example 1. MS(ES) m/z 320.0; HRMS: calcd for C₁₈H₁₆F₃NO+H⁺, 320.12567; found (ESI,[M+H]⁺), 320.1261.

Example 48 (1E)-3,3-dimethyl-5-[4-(trifluoromethyl)phenyl]indan-1-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-(trifluoromethyl)phenylboronic acid according to the procedure as described in example 1. MS(ES) m/z 320.0; HRMS: calcd for C₁₈H₁₆F₃NO+H⁺, 320.12567; found (ESI,[M+H]⁺), 320.1262.

Example 49 (1E)-5-[4-(dimethylamino)phenyl]-3,3-dimethylindan-1-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-(dimethylamino)phenyl boronicacid according to the procedure as described in example 1. MS (ES) m/z295.0; HRMS: calcd for C₁₉H₂₂N₂O+H⁺, 295.18049; found (ESI, [M+H]⁺),295.1815.

Example 50 (1E)-5-[3-(dimethylamino)phenyl]-3,3-dimethylindan-1-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 4-(dimethylamino)phenyl boronicacid according to the procedure as described in example 1. MS (ES) m/z295.1; HRMS: calcd for C₁₉H₂₂N₂O+H⁺, 295.18049; found (ESI, [M+H]⁺),295.182.

Example 51 (1E)-5-(3,4-difluorophenyl)-3,3-dimethylindan-1-one oxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3,4-difluorophenyl boronic acidaccording to the procedure as described in example 1. MS (ES) m/z 288.0;HRMS: calcd for C₁₇Hf₅F₂NO+H⁺, 288.11945; found (ESI, [M+H]⁺), 288.1203.

Example 52 (1E)-5-[3-(ethylsulfonyl)phenyl]-3,3-dimethylindan-1-oneoxime

The title compound was prepared from trifluoro-methanesulfonic acid3,3-dimethyl-1-oxo-indan-5-yl ester and 3-(ethylsulfonyl)phenyl boronicacid according to the procedure as described in example 1. MS (ES) m/z344.0; HRMS: calcd for C₁₉H₂₁NO₃S+H⁺, 344.13149; found (ESI, [M+H]⁺),344.1317.

Example 53 Pharmacology

The compounds of this invention were tested in the relevant assay asdescribed below and their potency are in the range of 0.01 nM to 5

M in the in vitro assays and 0.001 to 300 mg/kg in the in vivo assays.

TABLE 1 Potency of representative 5-aryl-indan-1-one oximes and analogsas PR modulators in progesterone induced T47D alkaline phosphataseassay.

Example Alk. Phos. Alk. Phos. No. R₁ R₂ R IC₅₀ (nM) % inh @ 3 μM¹ 3 Me H— 65.0 — 6 H H 3-CN ~3000 — 7 H H 4-CN ~1000 — 15 H H — 32.6 — 33 Me Me4-Cl — 100  34 Me Me 4-Me — 68 35 Me Me 4-OMe — 63 36 Me Me 3-Cl — 70 37Me Me 3-Me — 65 38 Me Me 3-OMe — 42 39 Me Me 3-Cl, 5-Cl — 30 40 Me Me2-Cl — 62 41 Me Me 3-Cl, 4-Cl 455.6 — 42 Me Me 2-Cl, 3-Cl — 100 ¹Percent inhibition of the progesterone (1 nM) induced alkalinephosphatase activity using 3 μM of the test compound is measured.(1) T47D Cell Proliferation Assay

(a) Objective: Determination of progestational and antiprogestationalpotency by using a cell proliferation assay in T47D cells. A compound'seffect on DNA synthesis in T47D cells is measured.

(b) Methods:

A. Reagents

-   -   (i) Growth medium: DMEM:F12 (1:1) (GIBCO, BRL) supplemented with        10% (v/v) fetal bovine serum (not heat-inactivated), 100U/mL        penicillin, 100 mg/mL streptomycin, and 2 mM GlutaMax™ media        (GIBCO, BRL).    -   (ii) Treatment medium: Minimum Essential Medium (MEM)        (#51200-038GIBCO, BRL) phenol red-free supplemented with 0.5%        charcoal stripped fetal bovine serum, 100U/mL penicillin, 200        mg/mL streptomycin, and 2 mM GlutaMax™ media (GIBCO, BRL).

B. Cell Culture

-   -   Stock T47 D cells are maintained in growth medium. For BrdU        incorporation assay, cells are plated in 96-well plates (Falcon,        Becton Dickinson Labware) at 10,000 cells/well in growth medium.        After overnight incubation, the medium is changed to treatment        medium and cells are cultured for an additional 24 hours before        treatment. Stock compounds are dissolved in appropriate vehicle        (100% ethanol or 50% ethanol/50% DMSO), subsequently diluted in        treatment medium and added to the cells. Progestin and        antiprogestin reference compounds are run in full dose-response        curves. The final concentration of vehicle is 0.1%. In control        wells, cells receive vehicle only. Antiprogestins are tested in        the presence of 0.03 nM trimegestone, the reference progestin        agonist. Twenty-four hours after treatment, the medium is        discarded and cells are labeled with 10 mM BrdU (Amersham Life        Science, Arlington Heights, Ill.) in treatment medium for 4        hours.

C. Cell Proliferation Assay

-   -   At the end of BrdU labeling, the medium is removed and BrdU        incorporation is measured using a cell proliferation ELISA kit        (#RPN 250, Amersham Life Science) according to manufacturer's        instructions. Briefly, cells are fixed in an ethanol containing        fixative for 30 minutes, followed by incubation in a blocking        buffer for 30 minutes to reduce background. Peroxidase-labeled        anti-BrdU antibody is added to the wells and incubated for 60        minutes. The cells are rinsed three times with PBS and incubated        with 3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10-20        minutes depending upon the potency of tested compounds. Then 25        L of 1 M sulfuric acid is added to each well to stop color        reaction and optical density is read in a plate reader at 450 nm        within 5 minutes.

D. Analysis of Results

-   -   Square root-transformed data are used for analysis of variance        and nonlinear dose response curve fitting for both agonist and        antagonist modes. Huber weighting is used to downweight the        effects of outliers. EC₅₀ or IC₅₀ values are calculated from the        retransformed values. JMP software (SAS Institute, Inc.) is used        for both one-way analysis of variance and non-linear dose        response analyses in both single dose and dose response studies.

E. Reference Compounds

-   -   Trimegestone and medroxyprogesterone acetate (MPA) were        reference progestins and RU486 is the reference antiprogestin.        All reference compounds were run in full dose-response curves        and the EC₅₀ or IC₅₀ values were calculated.

TABLE 2 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for individual studies EC₅₀ 95% CI Compound Exp (nM) SElower upper Trimegestone 1 0.017 0.003 0.007 0.040 2 0.014 0.001 0.0110.017 3 0.019 0.001 0.016 0.024 MPA 1 0.019 0.001 0.013 0.027 2 0.0170.001 0.011 0.024

TABLE 3 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU486 EC₅₀ 95% CI Compound Exp (nM) SE lower upperRU486 1 0.011 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 3 0.018 0.0010.014 0.022 EC₅₀: Concentration of a compound that gives half-maximalincrease in BrdU incorporation with SE; IC₅₀: Concentration of acompound that gives half-maximal decrease in 0.1 trimegestone inducedBrdU incorporation with SE(2) Rat Decidualization Assay

(a) Objective: This procedure is used to evaluate the effect ofprogestins and antiprogestins on rat uterine decidualization and comparethe relative potencies of various test compounds.

(b) Methods

A. Reagents

-   -   Test compounds are dissolved in 100% ethanol and mixed with corn        oil (vehicle). Stock solutions of the test compounds in oil (the        Mazola™ oil) are then prepared by heating (˜80° C.) the mixture        to evaporate ethanol. Test compounds are subsequently diluted        with 100% corn oil or 10% ethanol in corn oil prior to the        treatment of animals. No difference in decidual response is        found when these two vehicles are compared.

B. Animals (RACUC Protocol #5002)

-   -   Ovariectomized mature female Sprague-Dawley rats (˜60-day old        and 230 g) are obtained from Taconic (Taconic Farms, N.Y.)        following surgery. Ovariectomy is performed at least 10 days        prior to treatment to reduce circulating sex steroids. Animals        are housed under 12 hours light/dark cycle and given standard        rat chow and water ad libitum.

C. Treatment

-   -   Rats are weighed and randomly assigned to groups of 4 or 5        before treatment. Test compounds in 0.2 mL vehicle are        administered by subcutaneous injection in the nape of the neck        or by gavage using 0.5 mL. The animals are treated once daily        for seven days. For testing antiprogestins, animals are given        the test compounds and an EC₅₀ dose of progesterone (5.6 mg/kg)        during the first three days of treatment. Following decidual        stimulation, animals continue to receive progesterone until        necropsy four days later.

D. Dosing

-   -   Doses are prepared based upon mg/kg mean group body weight. In        all studies, a control group receiving vehicle is included.        Determination of dose-response curves is carried out using doses        with half log increases (e.g. 0.1, 0.3, 1.0, 3.0 mg/kg).

E. Decidual Induction

-   -   Approximately 24 hours after the third injection,        decidualization is induced in one of the uterine horns by        scratching the antimesometrial luminal epithelium with a blunt        21 G needle. The contralateral horn is not scratched and serves        as an unstimulated control. Approximately 24 hours following the        final treatment, rats are sacrificed by CO₂ asphyxiation and        body weight measured. Uteri are removed and trimmed of fat.        Decidualized (D-horn) and control (C-horn) uterine horns are        weighed separately.

F. Analysis of Results

-   -   The increase in weight of the decidualized uterine horn is        calculated by D-horn/C-horn and logarithmic transformation is        used to maximize normality and homogeneity of variance. The        Huber M-estimator is used to down weight the outlying        transformed observations for both dose-response curve fitting        and one-way analysis of variance. JMP software (SAS Institute,        Inc.) is used for both one-way ANOVA and non-linear        dose-response analyses.

G. Reference Compounds

-   -   All progestin reference compounds are run in full dose-response        curves and the EC₅₀ for uterine wet weight is calculated.

TABLE 4 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals for individual studies EC₅₀ 95% CI Compound Exp (nM) SE lowerupper Progesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.763-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25 3 0.060.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12 0.02 0.090.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1 0.42 0.03 0.290.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61

TABLE 5 Estimated average EC₅₀, standard error, and 95% confidenceintervals for dose-response curves of 3 reference compounds EC₅₀ 95% CICompound (mg/kg, s.c.) SE lower upper Progesterone 5.62 0.62 4.55 7.003-Ketodesogestrel 0.10 0.02 0.07 0.14 Levonorgestrel 0.10 0.01 0.08 0.12

TABLE 6 Estimated IC₅₀, standard error, and 95% confident interval forthe antiprogestin, RU 486 IC₅₀ 95% CI Compound Exp. (mg/kg, p.o.) SElower upper RU486 1 0.21 0.07 0.05 0.96 2 0.14 0.02 0.08 0.27Concentration: Compound concentration in assay (default-mg/kg bodyweight)

Route of administration: Route the compound is administered to theanimals

Body weight: Mean total animal body weight (default-kg)

D-horn: Wet weight of decidualized uterine horn (default-mg)

C-horn: Wet weight of control uterine horn (default-mg)

Decidual response: [(D−C)/C]×100%

Progestational activity: Compounds that induce decidualizationsignificantly (p<0.05) compared to vehicle control are considered active

Antiprogestational activity: Compounds that decrease EC₅₀ progesteroneinduced decidualization significantly (p<0.05)

EC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal increase in decidual response (default-mg/kg)

IC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal decrease in EC₅₀ progesterone induced decidual response(default-mg/kg)

(3) PRE-Luciferase Assay in CV-1 Cells

(a) Objective: To determine a compound's progestational orantiprogestational potency based on its effect on PRE-luciferasereporter activity in CV-1 cells co-transfected with human PR andPRE-luciferase plasmids.

(b) Methods

A. Reagents

-   -   (i) Culture medium:        -   Growth medium: DMEM (BioWhittaker) containing 10% (v/v)            fetal bovine serum (heat inactivated), 0.1 mM MEM            non-essential amino acids, 100U/mL penicillin, 100 mg/mL            streptomycin, and 2 mM the GlutaMax™ reagent (GIBCO, BRL).        -   Experimental medium: DMEM (BioWhittaker), phenol red-free,            containing 10% (v/v) charcoal-stripped fetal bovine serum            (heat-inactivated), 0.1 mM MEM non-essential amino acids,            100U/mL penicillin, 100 mg/mL streptomycin, and 2 mM the            GlutaMax™ reagent (GIBCO, BRL).

B. Cell Culture, Transfection, Treatment, and Luciferase Assay

-   -   Stock CV-1 cells are maintained in growth medium.        Co-transfection is done using 1.2×10⁷ cells, 5 mg pLEM plasmid        with hPR-B inserted at SphI and BamHI sites, 10 mg pGL3 plasmid        with two PREs upstream of the luciferase sequence, and 50 mg        sonicated calf thymus DNA as carrier DNA in 250 mL.        Electroporation is carried out at 260 V and 1,000 mF in a Biorad        Gene Pulser® II instrument. After electroporation, cells are        resuspended in growth medium and plated in 96-well plate at        40,000 cells/well in 200        L. Following overnight incubation, the medium is changed to        experimental medium. Cells are then treated with reference or        test compounds in experimental medium. Compounds are tested for        antiprogestational activity in the presence of 3 nM        progesterone. Twenty-four hours after treatment, the medium is        discarded and cells are washed three times with D-PBS (GIBCO,        BRL). Fifty mL of cell lysis buffer (Promega, Madison, Wis.) is        added to each well and the plates are shaken for 15 minutes in a        Titer Plate Shaker (Lab Line Instrument, Inc.). Luciferase        activity is measured using luciferase reagents from Promega.

C. Analysis of Results

-   -   Each treatment consists of at least 4 replicates. Log        transformed data are used for analysis of variance and nonlinear        dose response curve fitting for both agonist and antagonist        modes. Huber weighting is used to downweight the effects of        outliers. EC₅₀ or IC₅₀ values are calculated from the        retransformed values. JMP software (SAS Institute, Inc.) is used        for both one-way analysis of variance and non-linear response        analyses.

D. Reference Compounds

-   -   Progesterone and trimegestone are reference progestins and RU486        is the reference antiprogestin. All reference compounds are run        in full dose-response curves and the EC₅₀ or IC₅₀ values are        calculated.

TABLE 7 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three individual studiesEC₅₀ 95% CI Compound Exp (nM) SE lower upper Progesterone 1 0.616 0.0260.509 0.746 2 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.00943 0.0067 0.0003 0.0055 0.0082

TABLE 8 Estimated IC₅₀, standard error (SE), and 95% confident interval(CI) for the antiprogestin, RU486 from three individual studies IC₅₀ 95%CI Compound Exp (nM) SE lower upper RU486 1 0.028 0.002 0.019 0.042 20.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027

Progestational activity: Compounds that increase PRE-luciferase activitysignificantly (p<0.05) compared to vehicle control are consideredactive.

Antiprogestational activity: Compounds that decrease 3 nM progesteroneinduced PRE-luciferase activity significantly (p<0.05).

EC₅₀: Concentration of a compound that gives half-maximal increasePRE-luciferase activity (default-nM) with SE.

IC₅₀: Concentration of a compound that gives half-maximal decrease in 3nM progesterone induced PRE-luciferase activity (default-nM) with SE.

(4) T47D Cell Alkaline Phosphatase Assay

(i) Purpose: To identify progestins or antiprogestins by determining acompound's effect on alkaline phosphatase activity in T47D cells.

(ii) Methods

A. Reagents

-   -   (i) Culture Medium:        -   DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 5% (v/v)            charcoal stripped fetal bovine serum (not heat-inactivated),            100U/mL penicillin, 100 mg/mL streptomycin, and 2 mM the            GlutaMax™ reagent (GIBCO, BRL).    -   (ii) Alkaline phosphatase assay buffer:        -   I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% the Triton™ X-100            reagent;        -   II. 0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl            phosphate (Sigma).

B. Cell Culture and Treatment

-   -   Frozen T47D cells were thawed in a 37° C. water bath and diluted        to 280,000 cells/mL in culture medium. To each well in a 96-well        plate (Falcon, Becton Dickinson Labware), 180        L of diluted cell suspension was added. Twenty        L of reference or test compounds diluted in the culture medium        was then added to each well. When testing for progestin        antagonist activity, reference antiprogestins or test compounds        were added in the presence of 1 nM progesterone. The cells were        incubated at 37° C. in a 5% CO₂/humidified atmosphere for 24        hours.    -   Note: For high throughput screening, one concentration of each        compound was tested at 0.3 mg/mL. Based on an average molecular        weight of 300 g/mol for the compounds in the library, the        concentration was approximately 1 mM. Subsequently, active        compounds were tested in dose response assays to determine EC₅₀        or IC₅₀.

C. Alkaline Phosphatase Enzyme Assay

-   -   At the end of treatment, the medium was removed from the plate.        Fifty        L of assay buffer I was added to each well. The plates were        shaken in a titer plate shaker for 15 minutes. Then 150        L of assay buffer II was added to each well. Optical density        measurements were taken at 5 minute intervals for 30 minutes at        a test wavelength of 405 nM.

D. Analysis of Results—Analysis of Dose-Response Data

-   -   For reference and test compounds, a dose response curve was        generated for dose (X-axis) vs. the rate of enzyme reaction        (slope) (Y-axis). Square root-transformed data were used for        analysis of variance and nonlinear dose response curve fitting        for both agonist and antagonist modes. Huber weighting was used        to downweight the effects of outliers. EC₅₀ or IC₅₀ values were        calculated from the retransformed values. JMP software (SAS        Institute, Inc.) was used for both one-way analysis of variance        and non-linear dose response analyses in both single dose and        dose response studies.

E. Reference Compounds

-   -   Progesterone and trimegestone were reference progestins and        RU486 was the reference antiprogestin. All reference compounds        were run in full dose response curves and the EC₅₀ or IC₅₀        values were calculated.

TABLE 9 Estimated EC₅₀, standard error (SE), and 95% confidenceintervals (CI) for reference progestins from three independentexperiments EC₅₀ 95% CI Compound Exp (nM) SE lower upper Progesterone 10.839 0.030 0.706 0.996 2 0.639 0.006 0.611 0.669 3 1.286 0.029 1.1581.429 Trimegestone 1 0.084 0.002 0.076 0.091 2 0.076 0.001 0.072 0.080 30.160 0.004 0.141 0.181

TABLE 10 Estimated IC₅₀, standard error, and 95% confident interval forthe reference antiprogestin RU486 from three independent experimentsIC₅₀ 95% CI Compound Exp (nM) SE lower upper RU486 1 0.103 0.002 0.0920.115 2 0.120 0.001 0.115 0.126 3 0.094 0.007 0.066 0.134

All publications cited in this specification are incorporated herein byreference. While the invention has been described with reference toparticular embodiments, it will be appreciated that modifications can bemade without departing from the spirit of the invention. Suchmodifications are intended to fall within the scope of the appendedclaims.

1. A compound of formula I:

wherein: R₁ and R₂ are, independently, selected from the groupconsisting of H, halogen, C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl,C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, aryl, and substituted aryl;provided both of R₁ and R₂ are not H; or R₁ and R₂ arc fused to form (a)or (b) (a) a carbon-based 3 to 6 membered saturated spirocyclic ring; or(b) a carbon-based 3 to 6 membered spirocyclic ring having in itsbackbone one or more carbon-carbon double bonds; wherein rings (a)-(b)are optionally substituted by 1 to 3 substituents selected from thegroup consisting of F, Cl, and C₁ to C₃ alkyl; R₃ is a 5 memberedheteroaryl ring consisting of carbon atoms and 1 to 3 heteroatomsselected from the group consisting of O, S, SO, SO₂ and NR^(C) andsubstituted with 0 to 3 substituents selected from the group consistingof H, halogen, CN, NO₂, OH, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁to C₃ alkylamino, C═NOR^(C), COR^(D), and NR^(C)COR^(D); R^(C) isabsent, H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, CN, or COR^(D);R^(D) is H, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, or C₁ to C₃ alkylamino; R₄is H, halogen, CN, OH, NO₂, alkoxy, or lower alkyl; R₅ is H or loweralkyl; R₆, R₇, R₈, and R₉ are, independently, H, F, or C₁ to C₃ loweralkyl; n is 0 or 1; or a pharmaceutically acceptable salt thereof. 2.The compound according to claim 1, wherein: R₁ and R₂ are,independently, H or C₁ to C₆ alkyl; R₃ is a 5 membered heteroaryl ringconsisting of carbon atoms and 1 NR^(C) heteroatom; R^(C) is C₁ to C₄alkyl; R₄ is H; R₅ is H or C₁ to C₃ alkoxy.
 3. The compound according toclaim 2, wherein R₅ is H.
 4. The compound according to claim 1, wherein:R₁ and R₂ are, independently, H or C₁ to C₆ alkyl; R₃ is a 5 memberedheteroaryl ring consisting of carbon atoms and 1 NR^(C) heteroatom andsubstituted with 1 CN group; R^(C) is C₁ to C₄ alkyl; R₄ is H; R₅ is Hor C₁ to C₃ alkoxy.
 5. The compound according to claim 1, wherein: R₁and R₂ are, independently, C₁ to C₆ alkyl, CF₃, CF₂CF₃, or C₃ to C₆cycloalkyl; or R₁ and R₂ are fused to form a carbon-based 3 to 6membered saturated spirocyclic ring; R₄ is H, halogen, CN, OH, or NO₂;R₅ is H, alkyl, or perfluoroalkyl; R₆, R₇, R₈, and R₉ are,independently, H or F.
 6. The compound according to claim 5, wherein R₃is 1-methyl-2-cyanopyrrole.
 7. The compound according to claim 1,wherein R₃ is 1-methyl-2-cyano-pyrrole.
 8. The compound according toclaim 1, wherein R₃ is 3,5-dimethylisoxazole.
 9. The compound accordingto claim 1, wherein R₃ is of the structure:

wherein: U is O, S, or NR^(C); R^(C) is H, C₁ to C₄ alkyl, or COR^(D);R^(D) is C₁ to C₄ alkyl; X′ is selected from the group consisting ofhalogen, CN, NO₂, C₁ to C₃ alkyl, and C₁ to C₃ alkoxy; and Y′ isselected from the group consisting of H and C₁ to C₄ alkyl.
 10. Thecompound according to claim 1 selected from the group consisting of5-[(1E)-1-(hydroxyimino)-3-methyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;5-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;and (1E)-5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-one oxime.11. The compound according to claim 1 which is5-[(5E)-5-(hydroxyimino)-5,6,7,8-tetrahydronaphthalen-2-yl]-1-methyl-1H-pyrrole-2-carbonitrile.12. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 13. A pharmaceutically useful kitadapted for daily oral administration which comprises: (a) a first phaseof from 14 to 21 daily dosage units of a progestational agent equal inprogestational activity to about 35 to about 150 μg levonorgestrel; (b)a second phase of from 1 to 11 daily dosage units of a compound offormula I, each daily dosage unit containing said compound at a dailydosage of from about 2 to 50 mg, wherein said compound of formula I is:

wherein R₁ and R₂ are, independently, selected from the group consistingof H, halogen, C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, aryl, and substituted aryl; provided bothof R₁ and R₂ are not H; or R₁ and R₂ are fused to form (a) or (b): (a) acarbon-based 3 to 6 membered saturated spirocyclic ring; or (b) acarbon-based 3to 6 membered spirocyclic ring having in its backbone oneor more carbon-carbon double bonds; wherein rings (a)-(b) are optionallysubstituted by 1 to 3 substituents selected from the group consisting ofF, Cl, and C₁ to C₃ alkyl; R₃ is a 5 membered heteroaryl ring consistingof carbon atoms and 1 to 3 heteroatoms selected from the groupconsisting of O, S, SO, SO₂ and NR^(C) and substituted with 0 to 3substituents selected from the group consisting of H, halogen, CN, NO₂,OH, amino, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ alkylamino,C═NOR^(C), COR^(D), and NR^(C)COR^(D); R^(C) is absent, H, C₁ to C₄alkyl, substituted C₁ to C₄ alkyl, CN, or COR^(D); R^(D) is H, C₁ to C₃alkyl, C₁ to C₃ alkoxy, or C₁ to C₃ alkylamino; R₄ is H, halogen, CN,OH, NO₂, alkoxy, or lower alkyl; R₅ is H or lower alkyl; R₆, R₇, R₈, andR₉ are, independently, H, F, or C₁ to C₃ lower alkyl; n is 0 or 1; (c) athird phase of daily dosage units of an orally and pharmaceuticallyacceptable placebo; wherein the total number of the daily dosage unitsin the first phase, second phase and third phase equals 28.